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Stereotactic radiosurgery SRS Financials is an established non-invasive ablative therapy for brain metastases. Early clinical trials with SRS proved that tumor Regulate prices are superior to entire Mind radiotherapy (WBRT) on your own. Therefore, WBRT moreover SRS was greatly adopted for clients which has a restricted number of brain metastases (“minimal number” customarily suggests 1-4). Subsequent trials centered on answering no matter if WBRT upfront was necessary at all. Based upon latest randomized managed trials (RCTs) and meta-analyses comparing SRS alone to SRS moreover WBRT, adjuvant WBRT results in better intracranial Regulate; nonetheless, for the expenditure of neurocognitive operating and Standard of living. These adverse results of WBRT can also negatively impact on survival in younger patients. Based on the results of such studies, procedure has shifted to SRS by itself in clients having a limited range of metastases. On top of that, RCTs are assessing the part of SRS alone in people with >four brain metastases. New developments in SRS include fractionated SRS for giant tumors and The mixing of SRS with focused systemic therapies that cross the blood brain barrier and/or encourage an immune response. We current On this evaluation The existing substantial degree proof and rationale supporting SRS since the regular of look after sufferers with limited Mind metastases, and emerging apps of SRS.

Brain metastases are a significant cause of morbidity and mortality in patients with metastatic cancer, with an incidence of up to 65% during the course of illness [1, 2]. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer . Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. The development of brain metastases was viewed as an oncologic terminal event.

As systemic therapies have become more efficacious in patients with metastatic disease, improved survival rates are now being observed. In addition, the patterns of disease progression are shifting such that the incidence of brain metastases is increasing while extra-cranial disease remains controlled. This phenomena is likely a consequence of the central nervous system (CNS) being a sanctuary site from drug penetration. As a result, the management of brain metastases has become a major focus of research, with the intent to improve intra-cerebral control and decrease neurologic deaths.

Although the role of neurosurgery were established from the 1990s as a way to achieve regional Manage and extend survival, it absolutely was reserved to the minority of people presenting with just one metastasis and no other disorder past the Mind [4-seven]. Still lacking was a focal ablative non-invasive cure that may be utilized competently to some Considerably broader inhabitants of individuals with brain metastases. This established the phase for the event of stereotactic radiosurgery (SRS). SRS is really a focused ablative radiation remedy sent with sub-millimeter precision into the tumor localized in three-dimensions in 1-5 fractions.

The main focus of the evaluate would be to summarize The present substantial amount proof to make clear the function of SRS as ideal administration for clients presenting with confined Mind metastases. Furthermore, we provide an overview from the emerging programs of SRS because it carries on to evolve into a remedy different to WBRT, With all the intent To maximise neurcognitive operate and quality of life (QOL).

PATHOPHYSIOLOGY OF BRAIN METASTASES

Circulating tumor cells (CTCs) can disseminate from a Main tumor mass to type distant colonies by means of implantation at an ectopic web site, like the brain [eight-ten]. To take action calls for CTCs to arrest in the circulation, extravasate from the bloodstream or lymphatics into the brain, and survive and proliferate [eleven-thirteen]. The entire process of metastatic colonization requires a direct interaction of CTCs with endothelial cells and astrocytes during the Mind microenvironment. One example is, CTCs that have arrested inside the capillary bed immediate regional endothelial cells to remodel the adjacent atmosphere to market tumour mobile progress and invasion [14-sixteen]. Even further, metastatic tumour cells recruit systemic stromal cells, for example fibroblasts, to assist with early colonization , and co-decide community stromal cells, for example reactive astrocytes and microglia, to promote tissue invasion [fifteen, 18, 19]. Astrocytes within the tumour microenvironment could also play a job in safeguarding tumour cells from chemotherapy-induced cytotoxicity, through a nonetheless being defined system necessitating mobile-cell contact [twenty, 21]. Tumour cells, by means of launch of migration inhibitory element, interleukin-eight, and plasminogen activator inhibitor 1, induce astrocyte activation and modify the inflammatory milieu to boost tumor-mobile proliferation in vitro [22-24]. These molecular processes represent novel and understudied attainable therapeutic targets for your procedure of intracranial metastatic ailment.

SRS was initially an exceptionally resource intense therapy offered only at specialized facilities and indicated only for metastatic clients with a great lifestyle expectancy. The problem lay in prognosticating patients properly and as a result the Radiation Therapy Oncology Group (RTOG) recursive partitioning Investigation (RPA) [28, 29] was created. Based upon the patient's Karnofsky Functionality Position (KPS), age, status of the principal tumor and existence of extracranial disease, individuals ended up grouped into class 1, two or three with corresponding median survivals of 7.one, 4.2 and a pair of.three months, respectively. Though An important progress at some time, the RPA is now thought of overly simplistic as present oncologic decision generating is a lot more complex incorporating molecular, histological, clinical and radiographic condition qualities. You can find now much more refined classification instruments, such as the diagnosis-certain graded prognostic evaluation (DS-GPA). This technique provides histology-particular estimates of survival and can separate, as an example, by far the most favorable breast most cancers clients using an anticipated survival of 25 months (fantastic KPS and luminal B sort breast most cancers) in the minimum favorable sufferers with an predicted survival of 3 months (bad KPS and basal-like breast most cancers) . Even with advances in prognostication of people with brain metastases, doctors are still mainly unable to properly forecast very long-term survivors. A research asking pro physicians to estimate survival of a one hundred fifty sufferers with details about most cancers type, variety of brain metastases, neurological presentation, added-cranial disease status, KPS, RPA class, prior full-brain radiotherapy, and synchronous or metachronous presentation, confirmed that greater than 45% of predictions were off by over six months and 18% have been off by over twelve months . More improvements in prognostic assessments including the “liquid biopsy” (a non-invasive blood examination that will detect tumor DNA or RNA fragments or CTCs) are desired and in progress . These Merge Innovative affected person and tumor particular genomic info into your equation, so as to accomplish personalised survival predictions.

Medical procedures carries on to get a significant treatment method selection for individuals with constrained Mind metastases. It can be indicated when metastases are big (>3-four cm), or whenever a pathologic diagnosis is needed. In addition, surgical procedure is chosen from the existence of considerable edema demanding prolonged significant dose dexamethasone, or to likely reverse neurological deficits. Otherwise, The existing evidence implies the efficacy of SRS is ample to achieve durable regional Command that is certainly corresponding to surgical treatment. Despite the fact that there won't be any RCTs instantly comparing The 2, a number of trials are already described evaluating SRS to SRS with WBRT (Table 1), and it is A significant target of this evaluation.

HR: hazard ratio, WHO: planet wellness Business, KPS: Karnofsky functionality standing, WBRT: entire Mind radiotherapy, SRS: stereotactic radiosurgery, yr: 12 months, mos: months, NS: not important, NR: not recorded, NA: not applicable, HVLT-R: Hopkins Verbal Studying Test revised.

Patients during the observation group had either surgery by itself or SRS by yourself. Practical outcome wasn't analyzed independently by surgical treatment or SRS alone.

The main RCTs assessing SRS mimicked the look on the Preliminary surgical research for Mind metastases, and evaluated the addition of SRS to WBRT [33, 34]. These scientific studies verified that SRS improved community Management, along with a survival gain in chosen patients with one brain metastasis was revealed. These trials had been successful in shifting the paradigm from WBRT by yourself to WBRT furthermore SRS for people presenting with constrained Mind metastases and an excellent performance status.

The subsequent series of medical trials were being intended to response if WBRT was whatsoever important, and in contrast SRS by yourself to SRS with adjuvant WBRT. A few RCTs have already been claimed in sufferers presenting with nearly four metastases [35-37] along with a forth in summary variety . Aoyama et al. reported the initial RCT, randomizing 132 patients to SRS by itself (sixty five people) or WBRT additionally SRS (sixty seven people). The primary endpoint was brain tumor recurrence. Even though the one-year neighborhood Regulate rate was large with SRS by yourself at seventy three%, extra neighborhood Regulate with adjuvant WBRT at 89%, was noticed. Furthermore, adjuvant WBRT lowered the rate of distant intra-cranial relapse at one 12 months from sixty four% to forty two%. However, these gains in intra-cranial Handle did not translate into a bonus with respect to cognition, determined by Mini-Psychological Position Test (MMSE), nor survival. What's more, patients had better fees of necrosis and leukoencephalopathy in the WBRT arm. The trial was thus effective in offering the initial degree 1 evidence to clarify the relative impact of SRS by itself vs . SRS with WBRT.

In lieu of the standard endpoint of survival or intra-cranial Management, Chang et al. took a distinct technique and evaluated neurocognition as the principal endpoint. Importantly, the validated Hopkins Verbal Understanding Examination-Revised (HVLT-R) assessment tool, was utilized to evaluate neurocognitive working instead of the MMSE which is not a delicate examination for neurocognition . Fifty-eight people were being randomized to SRS by yourself (n = thirty) or WBRT in addition SRS (n = 28). Early stopping rules were being invoked for the interim Examination, as well as the study concluded that SRS by itself was favored with respect to the chance of neurocognitive decline at four months put up-remedy. This benefit was recognized despite the one yr neighborhood control and distant Mind Handle fees favoring adjuvant WBRT with absolute gains of 33% and 27%, respectively. The intracranial control results had been Consistent with the outcome from the Aoyama examine, but what was not anticipated was the survival gain observed during the SRS on your own arm. The median survival was fifteen months inside the SRS on your own arm and six months in the SRS with WBRT arm (p = 0.003). This survival result brought on the demo to undertake significant scrutiny with lots of arguing that the survival edge for SRS by itself was a result of imbalances involving The 2 arms, as a lot more people treated with SRS in addition WBRT experienced higher further-cranial (extra liver and adrenal metastases) and intracranial sickness (larger sized quantity of Mind metastases) .

The eu Business for Study and Therapy of Cancer (EORTC) also took another solution with their Key endpoint concentrating on practical independence . They utilized, having said that, the greater clinically acquainted Globe Well being Corporation (WHO) efficiency status (PS) scale, and calculated enough time to WHO PS deterioration to over two. This RCT concluded the addition of WBRT did not Increase the median length of functional independence (SRS by itself: 10.0 months vs SRS plus WBRT: nine.5 months). The secondary consequence of QOL, calculated Using the validated EORTC-QLQC30 Software, was observed to become even worse in people who acquired WBRT in several QOL domains . Importantly, these effects have been noticed Even with adjuvant WBRT decreasing the two-year community failure charge (31% to 19%), distant Mind failure (48% to 33%), and the necessity for salvage therapies (fifty one% vs. 16%). No sizeable variances in survival were observed albeit the demo was not powered to address survival.

These 4 trials have recognized the position of SRS on your own because the regular of treatment in people using a confined quantity of Mind metastases, but they have not been intended to Examine the influence of WBRT on Over-all survival.

The inclusion criteria throughout the RCTs evaluating SRS on your own to SRS as well as WBRT were equivalent (Desk one), however, the main endpoints have been wholly different, and no trial was designed to Assess Total survival. To raised explain the results of local Handle, distant brain Management and survival, a meta-Evaluation (MAL) was carried out by Tsao, Xu and Sahgal in 2012 . They documented hazard ratios for community Command and distant Mind Command favoring adjuvant WBRT at two.sixty one and a couple of.fifteen, respectively, but were being not able to mix the survival results because of restrictions in the way in which the data had been noted. Sahgal et al. then carried out a person client facts (IPD) MAL of a similar RCTs directed at analyzing cure outcomes on survival, and conduct sub-group analyses . With respect to General survival, a treatment effect was noticed favoring SRS by yourself in sufferers ≤50 many years. In more mature people, no survival drawback was observed with SRS alone. With regard to distant brain Command, a cure influence was also observed with risk reductions in the event of latest Mind metastases in older patients dealt with with WBRT, but no reward within the younger clients (≤50 decades) taken care of with WBRT. As predicted, nearby Regulate was improved with extra WBRT in all age teams. The concordance concerning a survival detriment and deficiency of advantage in distant Mind Command Even with therapy with WBRT, during the more youthful patients, led the authors to hypothesize that exposure into the identified harms of WBRT (discussed intimately below) may negatively impression affected person survival. This speculation is provocative, and remains to become validated.

By far the most convincing trial structure to verify the adverse outcomes of WBRT is always to randomize clients without having visualized brain metastases to observation or WBRT. This is finished in scientific tests analyzing prophylactic cranial irradiation (PCI) in equally small mobile lung most cancers (SCLC) [44, 45] and non-smaller cell lung most cancers (NSCLC) [46, forty seven]. PCI, not dissimilar on the addition of WBRT to SRS, is demonstrated to reduce the risk of intra-cranial relapse. Nonetheless, this obtain will come with the expense of the adverse effect on QOL. For example, major increases in tiredness, hunger decline, nausea and vomiting and leg weakness were noticed in individuals with extensive phase SCLC at six and 12 months post PCI . In addition, in locally Innovative NSCLC sufferers, a higher decrease in HVLT-R steps of rapid and delayed recall have been noticed even up to one yr write-up-PCI . With respect to lengthier-phrase adverse outcomes of WBRT, a devastating consequence could be the event of leukoencephalopathy. Certainly, radiation-induced dementia costs have already been noted to generally be as higher as 11% in extended-phrase brain metastases survivors (>12 months) soon after WBRT , and described to generally be greater in individuals taken care of with WBRT and SRS rather than SRS by yourself [35, fifty].

Abnormal N-methyl-D-aspartate (NMDA) receptor stimulation, comparable to the pathophysiology inherent to Parkinson's dementia , is postulated as a single mechanism detailing the adverse neurocognitive consequences of WBRT. As a technique to mitigate the chance, RTOG 0614 evaluated memantine, a neuroprotective agent that blocks pathologic stimulation of NMDA, in a considerable randomized placebo managed trial involving 554 individuals. At 24 weeks, 64% of sufferers with out memantine and 54% with memantine had cognitive purpose failure dependant on evaluation While using the HVLT-R. Even though the Principal endpoint did not achieve importance due to large attrition charge, there was a powerful craze (p = 0.059) supporting memantine remedy. Investigation of secondary endpoints confirmed that memantine significantly extended time to cognitive decline and yielded superior success for executive functionality, processing pace and delayed recognition at 24 weeks. Finally, these knowledge exhibit many individuals suffer cognitive dysfunction with WBRT, and that pharmacologic strategies to mitigate the danger by targeting identical pathways involved with Parkinson's dementia could be deserving of even more investigation.

Additional Perception into WBRTs’ mechanism of injury has come from a the latest Section 2 trial assessing hippocampal avoidance WBRT (HA-WBRT). Advanced fashionable radiation know-how was placed on Restrict dose publicity to the hippocampus to no more than 80% from the prescribed 30Gy in 10 fractions . This non-randomized stage two demo calculated neurocognitive purpose utilizing the HVLT-R, and compared outcomes to historic controls handled with typical WBRT from the RTOG demo databases. HA-WBRT resulted inside of a 7% decline within the suggest relative HVLT-R delayed remember, which was significantly reduce when compared to the thirty% drop received from historic controls. Though this analyze is encouraging with regard to restricting toxicity from WBRT, a randomized trial is necessary to completely realize the therapeutic benefit With this technologically complicated form of WBRT.

In 2012, the American Modern society for Therapeutic Radiation Oncology published an proof-centered guideline which has a number of suggestions within the management of Mind metastases . Due to the fact that time, the evidence from scientific trials has manufactured it clear that the popular up-front radiation therapy choice for clients with minimal brain metastases is SRS by yourself. Actually, the American Culture for Radiation Oncology (ASTRO) has not too long ago designed a definitive suggestion within their Choose Sensibly marketing campaign and endorse not to routinely increase adjuvant WBRT to SRS for restricted brain metastases . Furthermore, the lately revised Nationwide Extensive Cancer Network (NCCN) recommendations now assist SRS on your own even past Those people sufferers with “constrained” metastases, and do not specify an higher Restrict for the amount of metastases . The latter is forward considering; metastasis counting is probably going irrelevant and what issues is usually the suitability of your individual for SRS [fifty seven-59]. Thus, the onus is not on individuals that handle with SRS alone to justify the omission of WBRT; somewhat it really is on those who handle with WBRT inside of a SRS ideal affected individual.

WHAT ABOUT THE Client WITH MORE Comprehensive Mind METASTASES?

Previous specialized constraints in SRS technologies restricted the appliance of SRS to people with only a few brain metastases. Improvements in preset frame and frameless SRS technologies now enable cure of numerous metastases in an individual session [sixty, sixty one].

The initial big future review analyzing SRS by itself for multiple brain metastases was described in 2014 . Close to 1200 patients with 1-10 SRS eligible metastases had been taken care of with SRS by yourself working with Gamma Knife technological know-how (Elekta AB, Stockholm, Sweden). The analysis was broken down according to the 455 individuals with 1 metastases, 531 sufferers with 2 to 4 metastases and 208 with 5 to ten metastases. Survival, distant Mind relapse, and native Command fees were not substantially distinct in sufferers with five to 10 metastases compared to 2 to four metastases. These results are of major importance since they problem the dogma that clients with in excess of four metastases will never get pleasure from SRS by yourself resulting from shortened survival and can inevitably fall short elsewhere within the Mind. Hence, this demo delivers evidence to guidance SRS by itself in fantastic KPS clients with approximately ten metastases, supplied the person tumor quantity is no more than ten mL and < three cm in longest diameter, and the total cumulative volume of all tumors from the Mind is ≤15 mL. Several randomized trials are at this time evaluating WBRT alone versus SRS alone in comparable individuals, and in improvement is really a trial evaluating SRS on your own versus WBRT in addition SRS Enhance in patients with ten to twenty metastases.

Focused THERAPIES Together WITH Mind RADIATION

Compared to conventional chemotherapy, a number of targeted brokers have increased penetration in the blood-Mind barrier and yield response while in the brain. Dramatic improvements in disease Regulate are being noticed even for histologies for example melanoma that were previously considered don't just radioresistant but chemoresistant. Table two [sixty three-seventy five] summarizes selected medical trials evaluating the efficacy of qualified therapies by yourself or together with radiation therapy from the remedy of Mind metastases. Despite the fact that, with focused therapies by itself some remarkable reaction charges are noticed, development-cost-free-survival (PFS) rates usually are quick (< eight months). These outcomes are certainly not as well dissimilar from what has actually been accomplished with WBRT by yourself [33, fifty three]. The exception is in EGFR mutant non-smaller cell lung cancers taken care of which has a tyrosine kinase inhibitor. Within the review by Wu et al. for example, the median PFS was >15 months in EGFR mutant tumours dealt with with erlotinib.

Table 2. Summary of chosen trials of specific therapy by itself or in combination with brain radiation for that procedure of brain metastases.

PFS: progression cost-free survival, nPFS: neurologic development free survival, OS: Total survival, NSCLC: non-compact cell lung cancer, EGFR: epidermal progress component receptor, WBRT: whole brain radiotherapy, SRS: stereotactic radiosurgery, mos: months, wks: weeks, NS: not substantial, NR: not recorded, NA: not applicable

Few trials have combined focused therapies with radiation, and these are generally also summarized in Table 2. Despite the fact that, randomized proof remains to be missing, You can find suggestion from retrospective information that the combination could bring about enhanced outcomes. While in the retrospective Assessment of the possible cohort of people addressed with SRS for melanoma Mind metastases, the group that obtained ipilimumab had a significantly lengthier median survival (21.3 vs four.nine months) . Even so, caution must be exercised as concurrent qualified therapy and radiation cure might not be as innocuous as previously considered. The RCT assessing SRS with WBRT alone, vs . in combination with erlotinib or temozlomide, reported appreciably better Quality 3 to five toxicity prices in The mix arm; a lot more importantly, survival was even worse although it didn't attain statistical importance . A substantial limitation of the research was which the focused therapy wasn't biomarker-driven and should partially account for your poor survival observed. Warning also must be taken as You can find evidence that Mind metastases and first tumors might harbor unique genetic alterations. In a single examine of 86 matched Mind metastases and primary tumors, clinically insightful alterations in fifty three% of brain metastases were not detected in the first tumor .

The emerging evidence indicates that qualified therapies will Perform a major role inside the procedure of brain metastases. We postulate that Despite the fact that qualified agents may not be productive in managing gross disease while in the Mind, they may be productive in managing micro-metastatic condition while in the Mind. Therefore, a logical strategy could possibly be to mix targeted therapies with SRS alone, overcoming the limitation of SRS in addressing micrometastatic condition from the Mind and resulting in less distant Mind failures. The subsequent number of years will generate thrilling information as there are a number of trials in progress employing this technique.

INNOVATIONS IN SRS - INDICATIONS AND Programs

As tumors get more substantial, SRS dosing is counter-intuitively reduced with respect to tumor Management, to keep up basic safety to the traditional Mind tissue; usually, the risk of radiation necrosis becomes prohibitive . As a result, tumors bigger than four cm have commonly been excluded from solitary portion SRS. In the event the tumors are non-operable, then these individuals happen to be handled with WBRT Regardless of its poor area Regulate. The arrival of non-invasive head immobilization gadgets, on-board graphic-steerage units and State-of-the-art radiation shipping computer software has bring about the apply of hypofractionated frameless stereotactic radiotherapy (SRT) [sixty, seventy eight]. In essence by fractionating, the safety profile with regard to the normal Mind tissue toxicity is improved, and the entire tumor dose can be escalated these that doses like 24Gy in 3 fractions and thirty-40Gy in 5 fractions are now not unusual. 1 fascinating retrospective collection noted bigger costs of Manage and lessen charges of toxicities with hypofractionated SRT (36Gy in six fractions) in comparison with one fraction SRS . Having said that, this apply remains in its infancy and we are wanting a RCT to determine whether one fraction SRS really should be reserved just for tiny metastases (e.g. one-two centimeters), as the information counsel worse community control for more substantial tumors [eighty, 81]. Figure one is definitely an illustration of the efficacy of hypofractionated SRT in a substantial tumor. This patient might have usually been excluded from one fraction SRS and handled with WBRT upfront (moreover or minus a SRS Increase), or operated upon.

A. MRI of 3.6cm suitable cerebellar metastases from lung most cancers. B. Extremely conformal treatment method plan Using the one hundred% (environmentally friendly line) and 80% (blue line) isodose lines wrapping tightly across the gross tumour (purple colorwash), and scheduling concentrate on volume (orange colorwash). The brainstem (blue colorwash) is spared from large dose. (B) MRI 2 months submit completion of radiation (30Gy in five fractions). C. Entire resolution of your tumour at one year.

In publish-operative sufferers, the exercise of routinely managing with WBRT is usually becoming outdated. There's escalating utilization of SRS into the write-up-operative surgical cavity as a method to spare people from the adverse effects of WBRT and to improve nearby Manage [82-ninety three]. At the Sunnybrook Odette Most cancers Heart, We have now adopted hypofractionated SRT as our common of care, delivering 30-35Gy in five fractions to the post-operative tumor mattress . Fractionation has the benefit of reducing the adverse outcomes to the normal tissues, given that the targets are generally substantial and irregularly shaped. Our Preliminary outcomes have shown one 12 months regional Handle prices of ∼eighty% in clients who've possibly recurred and re-operated upon just after past WBRT, or in sufferers with no prior record of WBRT and operated upon. There is an ongoing review assessing publish-surgical cavity one fraction SRS by itself compared to WBRT and could be a follow-defining research .

In the last various decades, scientific trials have knowledgeable us about the right management of patients with brain metastases. Initially, SRS was thought of an adjunct to WBRT in chosen patients presenting that has a restricted range of brain metastases. Having said that, the part of WBRT has considering the fact that been questioned as We now have learned of its probable to adversely impact QOL and neurocognition. Due to this fact, SRS on your own has emerged as The present conventional of care with Stage 1 proof to assistance its exercise. Current investigation is centered on the evaluation of broader programs of SRS to many scientific scenarios which were customarily regarded as absolute indications for WBRT. Such as, SRS alone is at the moment being evaluated inside the cure of five or more brain metastases, and in publish-operative sufferers. A completely new era of trials can also be emerging investigating the affect of specific therapies concurrent with SRS.

Scientific trials in patients with brain metastases are a major challenge as summarized through the latest stories within the Reaction Assessment in Neuro-Oncology (RANO) brain metastases group [95, 96]. They suggest for demo layout and reaction assessment that trials be tumor or biomarker distinct, that assessment be depending on contrast-enhanced MRI, that baseline and repeated neurocognitive and QOL testing be performed with validated and sensitive devices, that stratification be dependant on excess-cranial sickness position, Which acceptable timing be viewed as with regards to endpoint screening. Eventually, the oncology Local community has acknowledged that the development of Mind metastases is no more the terminal oncologic function on the previous.

CONFLICTS OF Curiosity, Monetary DISCLOSURES

Dr. Arjun Sahgal has received honorarium from former instructional seminars for Medtronic Kyphoplasty division and Elekta AB, Dr. Sahgal has also acquired analysis grants from Elekta AB, or else there are no conflicts of interest to reveal.

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